Chronic pain is a common problem that presents a major challenge to healthcare providers because of its complex natural history, unclear etiology, and poor response to therapy. Chronic pain is a poorly defined condition, and opinions vary regarding which duration qualifies a pain as chronic. Most clinicians consider ongoing pain lasting longer than 6 months as diagnostic, and others have used 3 months as the minimum criterion. In chronic pain, the duration parameter is used arbitrarily; some authors suggest that any pain that persists longer than the reasonable expected healing time for the involved tissues should be considered chronic pain. The pathophysiology of chronic pain is multifactorial and complex and still is poorly understood. Some have even suggested that chronic pain might be a learned behavioral syndrome that begins with a noxious stimulus that causes pain. Patients with several psychological syndromes (e.g., major depression, somatization disorder, hypochondriasis, conversion disorder) are prone to developing chronic pain. Pain is the most common complaint that leads patients to seek medical care, and chronic pain is not uncommon. Approximately 35% of Americans have some element of chronic pain, and approximately 50 million Americans are disabled partially or totally due to chronic pain.
Various neuromuscular, reproductive, gastrointestinal, and urologic disorders may cause or contribute to chronic pain. Sometimes multiple contributing factors may be present in a single patient. The modern concept of pain treatment emphasizes the significance of prophylactic prevention of pain, as pain is more easily prevented than it is relieved. Pain is generally controlled by the administration of short acting analgesic agents, steroids and non-steroidal anti-inflammatory drugs. Analgesic agents include opiates, agonistic-antagonistic agents, and anti-inflammatory agents.
A variety of therapeutics are available for the treatment of pain. As would be appreciated by one of skill, therapeutics vary in pharmacological profile and effectiveness, and a large number of compounds exist which may be used for the treatment of pain. Examples of dosages of individual compounds which have been administered for the treatment of pain are shown below in Table 1. Examples of a NMDA antagonist (dextromethorphan), atypical μ-opioid agonist (tramadol), and the anti-convulsant gabapentin, are shown below.
TABLE 1Dosages for Partial Pain ReliefPain Relief(percent of reduction in pain)DoseDiabeticCompoundmg/dayNeuropathyFibromyalgiaDextromethorphan400-480<50 (Sang 2002)<40 (Staud 2005)HydrobromideTramadol 400<35 (Sindrup 1999)<30 (Biasi 1998;HydrochlorideRussell 2000)Gabapentin3600<50 (Marchettini<50 (Lesley 2007)2004)
As shown above in Table 1, the above dosages were only effective in providing at most approximately a 35-50% reduction in pain. Unfortunately, several adverse side effects are associated with the drugs provided at the above dosages. These side effects include, e.g., dizziness, somnolence, and peripheral edema for gabapentin.
Harmful side effects are associated with most traditional analgesics at dosages effective for treating a neuropathy. As would be appreciated by one of skill, these side effects can include respiratory depression, disturbed sleep patterns, diminished appetite, seizures, and psychological and/or physical dependency. For example, the pharmacological management of acute postoperative pain and chronic pain syndromes has been traditionally based on various regimens of opiates and their congeners or NSAIDs. All opiates have side effects, of which the most dangerous are respiratory and cardiovascular depression associated with excessive sedation. NSAIDs may also induce side effects such as exacerbation of bleeding tendencies and the impairment renal function.
Accordingly, there is a need to provide methods and compositions for the treatment of acute or chronic pain which provide effective control of pain with reduced harmful side effects. Clearly, there is a need for improved compositions and methods for the effective treatment of neuropathic pain.